Standard formulations of naturally occurring medicinal agents or synthetic therapeutic agents that are insoluble in water generally involve on of two methods for the solubilization of the active ingredient. In some cases such compounds are solubilized by the judicious selection of various solvents in which the active ingredient is soluble. Alcohols, glycols, and glycerin have proven useful in dissolving and holding a large variety of insoluble compounds in solution. In other cases compounds that are either acidic or alkaline in nature are often solubilized by the formation of water-soluble salts. Alkaloids, for example, are generally formulated as their alkaloidal salts in preference to their galenical preparations since they are more stable in the form of a salt and do not precipitate on long standing.
Not infrequently acid salts of weakly basic organic therapeutic agents provide aqueous solutions which are acidic in nature and which are then unsuitable for use in parenteral compositions. Furthermore, certain therapeutic agents are less stable in acidic or weakly acidic aqueous solutions and the preparation of water-soluble and stable parenteral compositions for these compounds has been most difficult to attain. Attempts to prepare parenteral solutions for compounds of this type have previously been directed towards replacing the aqueous solvent with an oil, such as olive oil, or an alcohol, such as ethyl alcohol, glycerin, or with hydro-alcoholic mixtures thereof, as for example, a 30% propylene glycol solution. Such preparations have generally proven to be unsuitable due to their hydrothermic nature on injection and due to their tendency towards irritation and necrosis. Additionally, oil injections are difficult to sterilize and have a tendency to oxidize and become rancid.
I have discovered a novel system for the preparation of solubilized and stabilized aqueous compositions of waterinsoluble therapeutic agents which are suitable for parenteral administration. More particularly my invention concerns itself with therapeutic agents which are water-insoluble and which contain a tertiary nitrogen capable of being protonated. Such compounds when reacted or complexed with an excess amount of a lipophilic, liquid fatty acid form a liquid salt which can then be solubilized in water by means of a nonionic surfactant. Solutions so obtained are characterized as micellular solutions, and are optically clear, stable, capable of sterilization and suitable for use in a variety of parenteral compositions.